Dose range evaluation of liposomal nystatin and comparisons with amphotericin B and amphotericin B lipid complex in temporarily neutropenic mice infected with an isolate of Aspergillus fumigatus with reduced susceptibility to amphotericin B.

Hope Hospital, School of Medicine, University of Manchester, Salford M6 8HD, Manchester M8 6RB, United Kingdom.

Abstract

Using an isolate of Aspergillus fumigatus that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [P = 0.24] and 1 mg/kg [P < 0.0001]), ABLC (5 mg/kg [P = 0.014] and 1 mg/kg [P < 0.0001]), and amphotericin B deoxycholate (5 mg/kg [P = 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (P = 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [P = 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.

Study of activity of L-nystatin at cumulative doses ranging from 10 to 35 mg/kg compared with those of amphotericin B and empty liposomes (control). Plots are of cumulative mortality against time after AF65 infection and treatment with L-nystatin. □, L-nystatin at 5 mg/kg on days 1 to 7; ●, L-nystatin at 5 mg/kg on days 1, 2, 4, and 7; ○, L-nystatin at 2.5 mg/kg on days 1 to 7; ▴, L-nystatin at 2.5 mg/kg twice daily on days 1, 2, 4, and 7; ◊, L-nystatin at 2.5 mg/kg on days 1, 2, 4, and 7; ■, amphotericin B at 5 mg/kg days on 1, 2, 4, and 7; ×, no active treatment.

Study of activity of L-amphotericin at doses ranging from 1 to 50 mg/kg given four times to mice infected with strain AF65 compared with those of amphotericin B and dextrose (control). Plots are of cumulative mortality against time after AF65 infection and treatment with L-amphotericin. □, L-amphotericin at 50 mg/kg on days 1, 2, 4, and 7; ▵, L-amphotericin at 25 mg/kg on days 1, 2, 4, and 7; ⧫, L-amphotericin at 5 mg/kg on days 1, 2, 4, and 7; ◊, L-amphotericin at 1 mg/kg on days 1, 2, 4, and 7; ■, amphotericin B at 5 mg/kg on days 1, 2, 4, and 7; ×, no active treatment.

Study of activity of ABLC at doses ranging from 1 to 50 mg/kg given seven times to mice infected with AF65 compared with those of amphotericin B and dextrose (control). Plots are of cumulative mortality against time after AF65 infection and treatment with ABLC. □, ABLC at 50 mg/kg on days 1 to 7; ▵, ABLC at 25 mg/kg on days 1 to 7; ●, ABLC at 5 mg/kg on days 1 to 7; ○, ABLC at 1 mg/kg on days 1 to 7; ■, amphotericin B at 5 mg/kg on days 1, 2, 4, and 7; ×, no active treatment.

Comparison of treatment with two doses (1 and 5 mg/kg) of L-nystatin, L-amphotericin, ABLC, and amphotericin B with control treatments in a model of invasive aspergillosis caused by AF65 in temporarily neutropenic mice. For all groups except L-nystatin at 1 mg/kg and amphotericin B at 1 mg/kg, the data are from two experiments. Plots are of cumulative mortality against time after AF65 infection and various treatments. ▴, L-nystatin at 2.5 mg/kg twice daily on days 1, 2, 4, and 7; ▵, L-nystatin at 0.5 mg/kg twice daily on days 1, 2, 4, and 7; ⧫, L-amphotericin at 5 mg/kg on days 1, 2, 4, and 7; ◊, L-amphotericin at 1 mg/kg on days 1, 2, 4, and 7; ●, ABLC at 5 mg/kg on days 1 to 7; ○, ABLC at 1 mg/kg on days 1 to 7; ■, amphotericin B at 5 mg/kg on days 1, 2, 4, and 7; □, amphotericin B at 1 mg/kg on days 1, 2, 4, and 7; ×, no active treatment.